Prefrontal cortex (PFC) is a brain region critically involved in the control of high-level executive processes including information storage, novelty seeking and emotional control. Functions of PFC neurons are strongly influenced by dopaminergic inputs. Aberrant dopaminergic actions have been implicated in PFC abnormalities associated with mental disorders such as schizophrenia and Attention Deficit-Hyperactivity Disorder (ADHD). Several lines of evidence suggest that the dopamine D4 receptor, which is highly enriched in PFC neurons, plays an important and unique role in regulating PFC functions. However, little is known about the cellular mechanisms and functional consequences of D4 receptor-mediated signaling in PFC circuits. Our previous studies have found that D4 receptors exert a complex and dynamic regulation of CaMKII, a multifunctional enzyme that plays a central role in regulating several key postsynaptic targets required for learning and memory, such as AMPA receptors. Recently, we found that D4 receptors in PFC pyramidal neurons bi- directionally regulated AMPAR-mediated transmission in an activity-dependent manner, which involved CaMKII-regulated AMPAR trafficking on dendrites and synapses. Moreover, we found that D4 receptors in PFC layer I GABAergic interneurons suppressed the AMPAR-mediated response in an activity-independent manner, which involved distinct molecules and mechanisms. Thus, we hypothesize that D4 receptors play important roles in PFC functions by dynamically regulating synaptic transmission in a manner dependent on neuronal activity and cell types. Combined electrophysiological, pharmacological, biochemical and molecular analyses will be used to test this hypothesis. Since alterations of synaptic transmission might be the core feature of mental disorders, it is of crucial importance to unravel the role of D4 receptors in regulating synaptic functions. Elucidation of these mechanisms would provide a framework for understanding how the dopaminergic and glutamatergic systems may be mechanistically linked. Such knowledge would not only offer important insights into functional roles of D4 receptors in normal PFC network, but also shed light on the development of new pharmacological agents for the treatment of many diseases associated with dopaminergic dysfunction in PFC. PUBLIC HEALTH RELEVANCE: This study aims to reveal the unique physiological actions of dopamine D4 receptors in prefrontal cortex (PFC), a brain region critical for cognition and emotion. Results generated from this proposal would significantly improve our understanding on how D4 receptors in PFC dynamically regulate AMPAR-mediated synaptic transmission in a manner dependent on neuronal activity and cell types. Such knowledge would not only offer important insights into functional roles of D4 receptors in normal PFC network, but also shed light on the development of new pharmacological agents for the treatment of neuropsychiatric disorders associated with dopaminergic dysfunction in PFC, such as ADHD and schizophrenia.